The field of this invention s the synthesis of polynucleotides, particularly as carried out on insoluble supports (viz. a silica support). More specifically, the invention is concerned with phosphite triester chemistry as a means for rapid synthesis of oligonucleotides.
I have recently reviewed the state of the art with respect to the phosphite triester chemistry in the synthesis of oligodeoxyribonucleotides. For general background, reference may be had to this article. See Genetic Engineering, Vol. 5, Ed. Setlow & Hollaender, Plenum Press, 1983, pp. 191-207. In the current methodology, the problem is that CH.sub.3 OPCl.sub.2 is not highly selective in reaction with the 3'--OH of a protected nucleoside. As a consequence preparations of the active reagent yield mixtures containing the desired materials, 3'-3' coupled products (inert in the subsequent reaction), and unreacted CH.sub.3 OPCl.sub.2, which must be removed from the mixture by distillation or precipitation procedures, which are troublesome to carry out with these highly moisture-sensitive materials.
There has been a need for a more selective protecting group in reacting with the nucleoside derivatives. There has also been a need for more stable intermediates.
The trichlorodimethylethyl ester group has heretofore been employed for special purposes in the synthesis of oligonucleotides. See Koster et al., Nucleic Acids Symp. Ser. (1980) No. 7:39-60; and Kellner et al., Angew, Chem. Int. Ed Engle. (1981) 20 (617):577-578. However, this group has not heretofore been employed as an ester group for protecting nucleosides in which the phosphorus bridge is in phosphite (PO.sub.3) form, as distinguished from the phosphate (PO.sub.4) form.